EP0880518B1 - A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives - Google Patents

A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives Download PDF

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EP0880518B1
EP0880518B1 EP96940864A EP96940864A EP0880518B1 EP 0880518 B1 EP0880518 B1 EP 0880518B1 EP 96940864 A EP96940864 A EP 96940864A EP 96940864 A EP96940864 A EP 96940864A EP 0880518 B1 EP0880518 B1 EP 0880518B1
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formula
compound
product
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carbon atoms
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EP0880518A1 (en
EP0880518A4 (en
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Yemane Woldeselassie Andemichael
Neil Howard Baine
William Morrow Clark
Conrad John Kowalski
Michael Anthony Mcguire
Robert John Mills
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/26—Halogenosulfates, i.e. monoesters of halogenosulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
  • the present invention relates to an improved process for preparing indane carboxylates and cyclopentano[ b ]pyridine derivatives.
  • the present invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
  • indane carboxylates and cyclopentano[ b ]pyridine derivatives specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
  • This invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
  • This invention also relates to novel intermediates useful in preparing aromatic ring-fused cyclopentane derivatives.
  • This invention relates to an improved process for preparing indane carboxylates.
  • This invention also relates to novel intermediates useful in preparing indane carboxylates.
  • This invention relates to an improved process for preparing cyclopentano[ b ]pyridine derivatives.
  • This invention also relates to novel intermediates useful in preparing cyclopentano[ b ]pyridine derivatives.
  • This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt.
  • This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
  • This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt.
  • This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
  • the term 'aromatic ring-fused cyclopentane derivatives' as used herein, is meant the racemic compounds of Formula (1): wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R 1 is where R 3 and R 4 are independently H, OH, C 1-8 alkoxy, F,CF 3 or C 1-6 alkyl and R 5 is -OCH 2 CO 2 H or -OCH 2 CH 2 OH; R 2 is where R 3 and R 4 are as indicated above and Z is H, OH, or C 1-5 alkoxy; or a pharmaceutically acceptable salt thereof.
  • racemic compounds of Formula (1) are the compounds of Formula (17): wherein A, B, C, D, R 1 , R 2 and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
  • indane carboxylates as used herein is meant the racemic compounds of Formula (2): wherein R 1 , R 2 and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
  • racemic compounds of Formula (2) are the compounds of Formula (18): wherein R 1 , R 2 and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
  • cyclopentano[ b ]pyridine derivatives as used herein is meant the racemic compounds of Formula (3): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R 1 , R 2 and Z are as described in Formula (1); or a phannaceutically acceptable salt thereof.
  • racemic compounds of Formula (3) are the compounds of Formula (19): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R 1 , R 2 and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
  • Ph as used herein is meant phenyl
  • X c means a chiral auxiliary.
  • chiral auxiliary as used herein is meant a non-racemic functional group that imparts a diastereoselective reaction at a remote prochiral center of a molecule.
  • Chiral auxiliaries as used herein are formed by reaction with a compound of the formula HX c wherein X c is as described above. Examples of HX c as used herein include: 8-phenylmenthol (such as described in D. Comins et al. J. Org. Chem., vol.
  • N-substituted borane-2, 10-sultams such as described in W. Oppolzer J. Am. Chem. Soc., 112 2767 (1990)
  • 4-substituted or 4,5-substituted 2-oxazolidinones derived from amino acid derivatives such as phenylglycinol or valinol such as described in D. Evans et al. J. Am. Chem. Soc., 109 , 6881(1987) and in D. Evans et al. Tet.
  • racemic compounds of Formulas (1), (2) and (3) are prepared as described herein by substituting the chiral X c substituent, as used herein, with an achiral group, such as an alkoxy or amine group.
  • activation reaction' for use herein refers to the numerous reactions and reaction conditions known to those skilled in the art to effect the introduction of a Br, I, -OSO 2 CF 3 or a -OSO 2 F substituent.
  • (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid ethylene diamine salt (2:1) as used herein utilizes standard chemical terminology and refers to Compound (s)
  • indane carboxylates of Formula (18) of the current invention are prepared by methods outlined in the Schemes below and in the Examples from compounds of Formula (a): where R is H, OH, C 1-5 alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy.
  • R is H, OH, C 1-5 alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy.
  • Compounds of Formula (a) are known or can be prepared from readily available starting materials by those skilled in the art.
  • 'protected oxy group' and 'protected OH' as used herein, is meant any conventional blocking group in the art such as described in "Protective Groups in Organic Synthesis" by Theodora W. Greene. Wiley-Interscience, 1981, New York, provided that such protected oxy groups or such protected OH do not include moieties that render inoperative the presently invented process.
  • a preferred protected oxy group for use herein is benzyloxy.
  • a preferred protected OH for use herein is benzyloxy.
  • R when necessary or desired, R can be converted to a substituent of Z.
  • Reactions to convert R to Z are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways.
  • hydroxyl groups can be converted into C 1-5 alkoxy groups by alkylation.
  • Protected oxy groups can be deprotected and further reacted to form a substituent of Z.
  • the present invention provides an improved process for the production of indane carboxylates of Formula (18) as indicated in Schemes 1 and 2 below.
  • Scheme 1 outlines formation of indane carboxylates wherein R 5 is -OCH 2 CO 2 H, preferably the disodium salt, Compound (k).
  • R 3 and R 4 are as described in Formula (1), R is as described in Formula (a) and R 7 is Br, I, -OSO 2 CF 3 or -OSO 2 F.
  • Compounds of Formula (c) are prepared in one or more steps by treating a compound of Formula (a) in an activation reaction, preferably with bromine in methylene chloride, to introduce substituent R 7 .
  • Compounds of Formula (d) are prepared by reacting a compound of Formula (c) with an acid chloride, such as thionyl chloride, and using this product as an acylating agent in a reaction, such as a Grignard reaction with a compound of Formula (t) as defined on page 32, or a Friedel-Crafts reaction, such as described in Example 1, step (iii).
  • Compounds of Formula (e) are prepared by reacting a compound of Formula (d) with a chiral auxiliary in the presence of palladium(II) acetate/triphenylphosphine catalyst.
  • Compounds of Formula (i) are prepared by hydrogenating a compound of Formula (h) over palladium on carbon. Treating a compound of Formula (i) with methyl bromoacetate and potassium carbonate in acetone/methanol, followed by saponification/epimerization effected with lithium hydroxide monohydrate and acid workup yields the corresponding diacid of Formula (6) (preferably Compound (j) as used herein). Compounds of Formula (6) are treated with sodium hydroxide to give compounds of Formula (4) (preferably Compound (k) as used herein). Additionally, treating a compound of Formula (i) with ethylene carbonate/potassium carbonate in toluene at 90-115°C.
  • Scheme 2 outlines formation of indane carboxylates wherein R 5 is -OCH 2 CH 2 OH, preferably the ethylene diamine salt (2:1), Compound (s).
  • R 3 and R 4 are as described in Formula (1)
  • R is as described in Formula (a)
  • R 7 is Br, I, -OSO 2 CF 3 or -OSO 2 F.
  • the acid chloride of the compounds of Formula (c) from Scheme 1 are reacted in an acylation reaction, preferably in a Grignard reaction with a compound of Formula (v) prepared as described on page 33, to give compounds of Formula (1).
  • Compounds of Formula (m) are prepared by reacting a compound of Formula (1) with a chiral auxiliary in the presence of palladium(II) acetate/triphenylphosphine catalyst. Treatment of a compound of Formula (m) with an appropriately substituted 3,4-(methylenedioxy)phenylmagnesium bromide (which can be readily prepared from commercially available starting materials) and a copper complex, preferably a copper (I) salt such as CuCl, CuBr, CuCN or most preferably copper(I) bromide-dimethylsulfide complex (which is commercially available from the Aldrich Chemical Co.
  • an appropriately substituted 3,4-(methylenedioxy)phenylmagnesium bromide which can be readily prepared from commercially available starting materials
  • a copper complex preferably a copper (I) salt such as CuCl, CuBr, CuCN or most preferably copper(I) bromide-dimethylsulfide complex (which is commercially available from the Aldrich Chemical Co
  • racemic compounds of Formulas (1), (2) and (3) are prepared according to the methods outlined in Schemes (1) and (2) and in the Examples by substituting a compound of Formula (9): wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is H, OH, C 1-5 alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy, for the compound of Formula (a) and by substituting the chiral X c substituent of the chiral auxiliary with an achiral group, such as an alkoxy or amine group.
  • a compound of Formula (9) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is H, OH, C 1-5 alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy, for the compound of Formula (
  • an achiral group is substituted for the X c substituent of the chiral auxiliary in Schemes 1 and 2 to prepare compounds of Formula (2) and intermediates useful in preparing compounds of Formula (2).
  • the compounds of Formula (9) are utilized in Schemes 1 and 2, by substituting the chiral X c substituent of the chiral auxiliary with an achiral group, to prepare compounds of Formula (1) and intermediates useful in preparing compounds of Formula (1).
  • the compounds of Formula (9), wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, are utilized in Schemes 1 and 2, by substituting the chiral X c substituent of the chiral auxiliary with an achiral group, to prepare compounds of Formula (3) and intermediates useful in preparing compounds of formula (3).
  • cyclopentano[ b ]pyridine derivatives of Formula (19) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (9) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom.
  • Preferred among Formula (9) compounds when a nitrogen is present are those wherein A is nitrogen.
  • aromatic ring-fused cyclopentane derivatives of Formula (17) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (9) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom.
  • Preferred among Formula (9) compounds when a nitrogen is present are those wherein A is nitrogen.
  • Also prepared in synthesizing the cyclopentano[ ⁇ ]pyridine derivatives of Formula (19) are the novel intermediates of Formula (21): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R 3 and R 4 are as described in Formula (1), R is as described in Formula (a), R 6 is OH or protected OH, when R 5 is OCH 2 CH 2 OH and R 7 is Br, I, -OSO 2 CF 3 or -OSO 2 F.
  • compound (t) is prepared according to the following steps (as used below R 3 and R 4 are as described in Formula (1)):
  • compound (v) is prepared according to the following steps:
  • the most preferred compound (u) is prepared according to the following steps:
  • a 12 L 3-necked flask was changed with 500 g (3.62 mol) of 3-hydroxybenzoic acid, 4 L of acetonitrile and 435 g (10.88 mol) of sodium hydroxide in 1.1 L of water. Heated the resulting mix to 60 °C over 40 minutes. Over a 60 minute period the n-dipropyl sulphate (2.5 eq) was added via an addition funnel while maintaining the reaction temperature 65 - 70 °C. After 6 hours a second portion of sodium hydroxide in 1.0 L of H 2 O was added over 30 minutes within 65 - 70 °C. After another 1.0 L at 65 - 70 °C the acetonitrile was allowed to evaporate to one half its original volume.
  • reaction slurry is then heated to 50 °C to dissolve all solids, transferred to a separatory funnel and the organic phase separated, washed with 2 x 2 L H 2 O, 1 L 50% brine.
  • the organic solubles are concentrated in vacuo and chased with hexane to produce a crude solid which is recrystallized from 2800 mL 190 proof EtOH. Yield 1202.8 g of the 4-methoxy-2-hydroxy precursor of the title compound (85%, HPLC purity, 97.0% by area).
  • the reaction mixture was cooled to 115 °C where 2 L of water and 2 L of toluene were carefully added. The solution was allowed to stir for 7 hours under nitrogen. The reaction solution was warmed to 40 - 45 °C H 2 O (3.3 L) and toluene (3.3 L) was added at 50 °C then transferred warm to a 12 L separatory funnel. The separate organic layer was separated and the aqueous layer was washed with water (2 x 3.3 L). The organic layer was concentrated to yield a wet solid. This material was dissolved in 3.2 L of 190 ethanol. This solution was cooled to 0 - 5 °C. The precipitated solids were collected via filtration to yield 586 g (0.95 mol, 72%) of the above depicted compound.
  • the reaction was stirred at -35 °C for 2 hours and at -10 °C for one hour.
  • Aqueous ammonium acetate 100 mL of saturated solution
  • the organic layer was separated and the aqueous layer was extracted with t-butyl methyl ether (3 x 100 mL).
  • the combined organic layer was washed with ammonium hydroxide (25% solution) until the blue color no longer persisted.
  • the solvent was removed under vacuum and 50 mL toluene was added then was also removed under vacuum.
  • the residual oil was dissolved in 50 mL of IPA and 150 mL of hexanes was added.
  • the reaction was deemed to be complete when all the starting material had been converted to the title compound.
  • the slurry was filtered through 300 g of Aluminium oxide rinsing with 1250 mL of acetone. The resulting filtrate was concentrated under reduced pressure to a volume of approximately 500 mL.
  • the concentrate was diluted with 2000 mL of t-butyl methyl ether (TBME) then washed with 2 x 1000 mL portions of 5% aqueous citric acid followed by 1000 mL of saturated aqueous brine to afford 1720 g of (+)-methyl-(1S,2S,3S)-5-propoxy-1-(3,4-methylenedioxy-phenyl)-3-(2-carbomethoxy]methoxy-4-methoxyphenyl)indane-2-carboxylate (the cis alkylated diester intermediate to the above depicted compound) as a solution in TBME.
  • the white solid product was dissolved in 2 L of acetonitrile and concentrated to near dryness where most of the solid product crystallized from solution. The flask was stored in the refrigerator over night at 0 °C. The solid was filtered and washed with 15% acetonitrile/water (1 L) and dried in vacuo at 60 °C for 24 hours. The above depicted predominately optically pure compound was obtained as a white solid: 664.8 g (43.4% yield); mp 177-179 °C.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Plural Heterocyclic Compounds (AREA)
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EP96940864A 1995-11-08 1996-11-08 A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives Expired - Lifetime EP0880518B1 (en)

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US634595P 1995-11-08 1995-11-08
US6345P 1995-11-08
PCT/US1996/018846 WO1997017342A1 (en) 1995-11-08 1996-11-08 A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives

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EP0880518A1 EP0880518A1 (en) 1998-12-02
EP0880518A4 EP0880518A4 (en) 1999-07-28
EP0880518B1 true EP0880518B1 (en) 2003-04-02

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US20060281723A1 (en) * 1999-04-16 2006-12-14 Kafrissen Michael E Folic acid-containing pharmaceutical compositions, and related methods and delivery systems
CN102887808B (zh) * 2012-10-26 2014-12-10 华东师范大学 一种多取代茚醇衍生物的制备方法

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US3997540A (en) * 1975-07-21 1976-12-14 Burroughs Wellcome Co. O [(O-piperazinocarbonyl-phenyl)-thio]-benzoates
US4073912A (en) * 1976-10-12 1978-02-14 Smithkline Corporation Piperidylidene derivatives of benzo-fused xanthenes, thioxanthenes and dibenzoxepins and antipsychotic use thereof
EP0612244B1 (en) * 1991-11-05 2001-09-19 Smithkline Beecham Corporation Endothelin receptor antagonists
US5389620A (en) * 1993-08-18 1995-02-14 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives
ZA969363B (en) * 1995-11-08 1997-11-18 Smithkline Beecham Corp An improved process for preparing aromatic ring-fused cyclopentane derivatives.
AU1054297A (en) * 1995-11-08 1997-05-29 Smithkline Beecham Corporation A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives
US6022972A (en) * 1997-08-08 2000-02-08 Merck & Co., Inc. Pyridine propanoic acid derivatives
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US6031101A (en) * 1998-04-09 2000-02-29 Merck & Co., Inc. Oxidation process using tempo

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CN1084742C (zh) 2002-05-15
EP0880518A1 (en) 1998-12-02
JP2000500444A (ja) 2000-01-18
DE69627199T2 (de) 2004-01-29
ZA969408B (en) 1997-06-10
CZ141598A3 (cs) 1998-11-11
NZ323790A (en) 2000-02-28
IL124312A0 (en) 1998-12-06
BR9611540A (pt) 1999-03-02
US20020087011A1 (en) 2002-07-04
NO982090L (no) 1998-07-07
AU711450B2 (en) 1999-10-14
MX9803646A (es) 1998-10-31
CO4761056A1 (es) 1999-04-27
PL326699A1 (en) 1998-10-26
KR19990067376A (ko) 1999-08-16
ATE236151T1 (de) 2003-04-15
DE69627199D1 (de) 2003-05-08
WO1997017342A1 (en) 1997-05-15
US6479659B2 (en) 2002-11-12
TW466236B (en) 2001-12-01
HK1016588A1 (en) 1999-11-05
EP0880518A4 (en) 1999-07-28
HUP9901985A2 (hu) 1999-09-28
CN1206415A (zh) 1999-01-27
US6147232A (en) 2000-11-14
ES2191121T3 (es) 2003-09-01
AR005237A1 (es) 1999-04-28
US6288247B1 (en) 2001-09-11
NO982090D0 (no) 1998-05-07
AU1082097A (en) 1997-05-29
TR199800839T2 (enExample) 1998-08-21

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